Search for COVID-19 drugs boosted by SARS discovery

Date:
August 27, 2020
Source:
Walter and Eliza Hall Institute
Summary:
An extensive search and testing of current drugs and drug-like
compounds has revealed compounds previously developed to fight
SARS might also work against COVID-19.



FULL STORY ==========================================================================
An extensive search and testing of current drugs and drug-like compounds
has revealed compounds previously developed to fight SARS might also
work against COVID-19.


========================================================================== Using the National Drug Discovery Centre, researchers from the Walter
and Eliza Hall Institute identified drug-like compounds that could
block a key coronavirus protein called PLpro. This protein, found in all coronaviruses, is essential for the virus to hijack and multiply within
human cells, and disable their anti-viral defences.

Initially developed as potential treatments for SARS, the compounds
prevented the growth of the SARS-CoV-2 virus (which causes COVID-19)
in the laboratory.

The discovery, published in The EMBO Journal, was led by Professor David Komander, Professor Marc Pellegrini, Professor Guillaume Lessene and Dr
Theresa Klemm.

At a glance
* Australian researchers have identified a molecular target for
potential
new COVID-19 treatments
* A chemical compound, originally discovered to inhibit SARS,
shows promise
for halting the growth of the COVID-19 virus (SARS-CoV-2)
* The discoveries were made by leveraging the capabilities of the
National
Drug Discovery Centre and ANSTO's Australian Synchrotron, and may
underpin the development of new drugs for COVID-19
Targeting a key viral protein Coronaviruses, including the viruses that
cause COVID-19 and SARS, all contain a protein called PLpro, which allows
the virus to hijack human cells and disable their anti-viral defences.



========================================================================== Professor Komander said PLpro belonged to a family of proteins called 'deubiquitinases', which his team had studied for the last 15 years in
a range of diseases.

"When we looked at how SARS-CoV-2 functions, it became clear that the
PLpro deubiquitinase was a key component of the virus -- as it is in
other coronaviruses, including the SARS-CoV-1 virus, which causes SARS,"
he said.

"We quickly established the VirDUB program to investigate how PLpro
functions and what it looks like. These are critical first steps towards discovering new drugs that could be potential therapies for COVID-19."
Using ANSTO's Australian Synchrotron, the VirDUB team rapidly ascertained
how PLpro interacts with human proteins -- homing in on a target that
could be blocked by new drugs.

Discovering new medicines The National Drug Discovery Centre was critical
to rapidly search for drugs that could block PLpro.



==========================================================================
"We scanned thousands of currently listed drugs, as well as thousands
of drug- like compounds, to see if they were effective in blocking the SARS-CoV- 2 PLpro," Professor Komander said.

"While existing drugs were not effective in blocking PLpro, we discovered
that compounds developed in the last decade against SARS, could prevent
the growth of SARS-CoV-2 in pre-clinical testing in the laboratory."
The next step is to turn these compounds into drugs that could be used
to treat COVID-19, Professor Komander said.

"We now need to develop the compounds into medicines, and make sure they
are safe for patients.

"Importantly, drugs that are able to inactivate PLpro may be useful not
just for COVID-19 but may also work against other coronavirus diseases,
as they emerge in the future." The publication in The EMBO Journal
research was a multidisciplinary collaboration of research teams at
the Walter and Eliza Hall Institute of Medical Research, the National
Drug Discovery Centre, ANSTO's Australian Synchrotron, the Commonwealth Scientific and Industrial Research Organisation (CSIRO), the Oncode
Institute and Department of Cell and Chemical Biology (Leiden University,
The Netherlands).

The research was funded by Hengyi Pacific Pty Ltd, the Australian National Health and Medical Research Council and Medical Research Future Fund,
the Nederlandse Organisatie voor Wetenschappelijk Onderzoek (NWO),
and the Victorian Government.


========================================================================== Story Source: Materials provided by Walter_and_Eliza_Hall_Institute. Note: Content may be edited for style and length.


========================================================================== Journal Reference:
1. Theresa Klemm, Gregor Ebert, Dale J Calleja, Cody C Allison,
Lachlan W
Richardson, Jonathan P Bernardini, Bernadine GC Lu, Nathan W
Kuchel, Christoph Grohmann, Yuri Shibata, Zhong Yan Gan, James
P Cooney, Marcel Doerflinger, Amanda E Au, Timothy R Blackmore,
Gerbrand J Heden van Noort, Paul P Geurink, Huib Ovaa, Janet
Newman, Alan Riboldi‐Tunnicliffe, Peter E Czabotar,
Jeffrey P Mitchell, Rebecca Feltham, Bernhard C Lechtenberg,
Kym N Lowes, Grant Dewson, Marc Pellegrini, Guillaume Lessene,
David Komander. Mechanism and inhibition of the papain‐like
protease, PLpro, of SARS‐CoV‐2. The EMBO Journal,
2020; DOI: 10.15252/embj.2020106275 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2020/08/200827102153.htm

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